DESCRIPTION (Applicant's Description): The precise role of the endogenous immune system in controlling cancer development remains unclear. Tumor cells are generally thought to be non-immunogenic since they are of "self" origin. However, tumor-reactive lymphocytes can be isolated from patients with many types of cancer. It is unclear what role these lymphocytes play and why they fail to protect the host. Using a murine B cell leukemia/lymphoma (BCL1) model, the investigators have shown that a vigorous early anti-tumor T cell response develops even in a tumor-susceptible host (1). However, the nature of this non-protective response is different from the protective response produced in a MHC-matched tumor-resistant host. Susceptible and resistant hosts develop polarized T cell responses to BCL1 which correlate with clinical outcome (1). Thus, the nature of the anti-tumor immune response seems critical to its subsequent development and the eventual clinical outcome. BCL1 constitutes a versatile model to study why the endogenous immune response succeeds in controlling tumor development in some cases, but fails in others. In this proposal, the investigators will take a multi-faceted approach to understand the molecular basis of tumor recognition and the immune regulatory mechanisms which determine each response. They have developed a novel method of identifying antigen-specific T cells using peptide/MHC tetramers and will make these reagents to trace the developmental fates of BCL1-reactive T cells in each response. Finally, they will address how the tumor cells may change as the endogenous immune response develops and how they may actively participate in shaping this response. This knowledge will not only shed light on important biological processes, but may help bring cancer immunotherapy closer to reality.